The remarkable capacity of the liver to regenerate is a phenomenon of great biologic significance, and of clinical importance in the recovery from hepatic disease. Identification of the factors that control liver regeneration should have broad implications in biology and practical applications in clinical medicine. Recent studies in our laboratory have provided solid evidence for the existence of a hepatotrophic humoral factor in portal venous blood that is required for liver regeneration, is utilized (or degraded) by both regenerating and normal liver, is not inactivated systemically, and appears to arise endogenously from the splanchnic viscera. These findings have been confirmed by other workers. It now remains to determine the site of origin, mode of action and metabolism of the hepatotrophic portal blood factor (HPBF), and to isolate and identify it. The proposed research is aimed at these objectives through studies of the effects of organ ablation and portal blood partitioning on liver regeneration in single and double liver rat models, and ultimately through attempts to extract the humoral agent from portal blood and splanchnic organs using a rat bioassay model for testing stimulatory activity. The prevention of atrophy of the whole liver, a process of importance in liver transplantation, may or may not be related to liver regeneration. Recent evidence suggests that a substance in portal blood is required to maintain hepatic integrity and prevent atrophy, although this issue is not settled. It is important to determine whether or not prevention of whole liver atrophy involves cell proliferation and requires a portal blood factor identical to or different from the HPBF responsible for liver regeneration. The proposed research is aimed at answering these questions through the use of a double liver rat model in which the blood supply to auxiliary whole liver isografts is varied.